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Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies

Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradica...

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Autores principales: Salillas, Sandra, Galano-Frutos, Juan José, Mahía, Alejandro, Maity, Ritwik, Conde-Giménez, María, Anoz-Carbonell, Ernesto, Berlamont, Helena, Velazquez-Campoy, Adrian, Touati, Eliette, Mamat, Uwe, Schaible, Ulrich E., Gálvez, José A., Díaz-de-Villegas, María D., Haesebrouck, Freddy, Aínsa, José A., Sancho, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467567/
https://www.ncbi.nlm.nih.gov/pubmed/34576300
http://dx.doi.org/10.3390/ijms221810137
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author Salillas, Sandra
Galano-Frutos, Juan José
Mahía, Alejandro
Maity, Ritwik
Conde-Giménez, María
Anoz-Carbonell, Ernesto
Berlamont, Helena
Velazquez-Campoy, Adrian
Touati, Eliette
Mamat, Uwe
Schaible, Ulrich E.
Gálvez, José A.
Díaz-de-Villegas, María D.
Haesebrouck, Freddy
Aínsa, José A.
Sancho, Javier
author_facet Salillas, Sandra
Galano-Frutos, Juan José
Mahía, Alejandro
Maity, Ritwik
Conde-Giménez, María
Anoz-Carbonell, Ernesto
Berlamont, Helena
Velazquez-Campoy, Adrian
Touati, Eliette
Mamat, Uwe
Schaible, Ulrich E.
Gálvez, José A.
Díaz-de-Villegas, María D.
Haesebrouck, Freddy
Aínsa, José A.
Sancho, Javier
author_sort Salillas, Sandra
collection PubMed
description Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens.
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spelling pubmed-84675672021-09-27 Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies Salillas, Sandra Galano-Frutos, Juan José Mahía, Alejandro Maity, Ritwik Conde-Giménez, María Anoz-Carbonell, Ernesto Berlamont, Helena Velazquez-Campoy, Adrian Touati, Eliette Mamat, Uwe Schaible, Ulrich E. Gálvez, José A. Díaz-de-Villegas, María D. Haesebrouck, Freddy Aínsa, José A. Sancho, Javier Int J Mol Sci Article Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens. MDPI 2021-09-20 /pmc/articles/PMC8467567/ /pubmed/34576300 http://dx.doi.org/10.3390/ijms221810137 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Salillas, Sandra
Galano-Frutos, Juan José
Mahía, Alejandro
Maity, Ritwik
Conde-Giménez, María
Anoz-Carbonell, Ernesto
Berlamont, Helena
Velazquez-Campoy, Adrian
Touati, Eliette
Mamat, Uwe
Schaible, Ulrich E.
Gálvez, José A.
Díaz-de-Villegas, María D.
Haesebrouck, Freddy
Aínsa, José A.
Sancho, Javier
Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title_full Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title_fullStr Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title_full_unstemmed Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title_short Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies
title_sort selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: efficacy, synergy, resistance and mechanistic studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467567/
https://www.ncbi.nlm.nih.gov/pubmed/34576300
http://dx.doi.org/10.3390/ijms221810137
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